Over excitation of NMDA receptor channel complexes on postsynaptic neurons following excessive release of glutamic acid from synaptosomes and glutamic acid from synaptosomes and glial cells results in a massive calcium ion influx into the neuronal cells, which leads to their death. This is believed to occur under ischemic or hypoxic conditions such as stroke, hypoglycemic, cardiac arrest and physical trauma. An NMDA receptor antagonist might be therapeutically useful because it may minimize damage of the central nervous system induced by ischemic or hypoxic conditions. The NMDA receptor channel complex consists of at least three binding domains including glutamic acid (or NMDA) recognition site, channel blocking binding site, and strychnine-insensitive glycine binding type. Physiologically, a blockade of at least one of these sites terminates the channel opening of the NMDA receptor to prevent a calcium ion influx J. Med. Chem., 1994;37:3956-3968, R. Nagata, et al.
Excessive excitation by neurotransmitters may be responsible for the loss of neurons in cerebral vascular disorders such as cerebral ischemia or cerebral infarction resulting in a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatal, asphyxia anoxia, such as from near drowning, pulmonary surgery, and cerebral trauma, as well as lathyrism, Alzheimer's disease, and Huntington's disease. Such conditions likewise suggest the use of agents that may act as antagonists in the receptors identified above may lead to treatment of Amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain, and drug addiction. PCT/EPO 94/01492 having publication number WO94/26747 published Nov. 24, 1994, Watjen, et al.
L-glutamic acid, L-aspartic acid, and a number of other closely related amino acids have the ability to activate neurons in the nervous system. Therefor the vast majority of excitatory neurons in the mammalian CNS. Interaction with glutamic acid mediated neurotransmission is considered a useful approach in the treatment of neurological and psychiatric diseases. WO94/26746, published Nov. 24, 1994, Jacobsen, et al.
Tricyclic quinoxaline diones as glutamate receptor antagonists are described in WO93/08188, published Apr. 29, 1993, R. Magata, et al.
WO92/22552, published Dec. 23, 1992, Tenbrink, et al., discloses imidazolo quinoxaline materials that are useful an anxiolytic and sedative/hypnotic agents.
European Patent Application 627,434, published Dec. 7, 1994, R. Nagata, et al., discloses tricyclic quinoxaline dione derivatives which are selective antagonists of the glycine binding site of the NMDA receptor.
It is an object of the present invention to disclose AMPA/GLY antagonists which are useful as neuroprotective agents.
It is a further object of the present invention to describe novel conformationally constrained tricyclic quinoxaline dione derivatives.